CA2097482A1 - Thiosemicarbazonic acid esters - Google Patents
Thiosemicarbazonic acid estersInfo
- Publication number
- CA2097482A1 CA2097482A1 CA002097482A CA2097482A CA2097482A1 CA 2097482 A1 CA2097482 A1 CA 2097482A1 CA 002097482 A CA002097482 A CA 002097482A CA 2097482 A CA2097482 A CA 2097482A CA 2097482 A1 CA2097482 A1 CA 2097482A1
- Authority
- CA
- Canada
- Prior art keywords
- allyl
- methyl
- oxo
- ylidene
- thiazolidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/54—Nitrogen and either oxygen or sulfur atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Novel thiosemicarbazonic acid esters Abstract The invention relates to novel thiosemicarbazonic acid esters of formula I
Description
20974~.~
Novel thiosemicarbazonic acid esters The invention relates to novel thiosemicarbazonic acid esters of formula I
1~ R4 ~ N S
R I ~C = N ` N ~ C ` N ` R (I) wherein Rl and Rs are lower alkyl, lower aLk-2-en-1-yl or lower alk-2-yn-1-yl, R2 and R3 independently of one another are hydrogen or lower alkyl or together are lower aLIcylidene and R4 is lower alkyl, lower aLkoxy, lower aLk-2-en-1-yl, lower alk-2-yn-1-yl, aryl-lower alkyl, aryl-lower aLkenyl or lower aLI~oxycarbonyl-lower aLIcyl, and to the salts and tautomeric compounds and double-bond isomers thereof, to processes for the preparation of the said compounds, to pharmaceutical compositions comprising them and to their use as active ingredients in medicaments.
Hereinbefore and hereinafter, "lower" radicals and compounds are to be understood as being, for example, those having up to and including 7, preferably up to and including 4, carbon atoms (C atoms).
Lower aL~-2-en-1-yl is, for exarnple, C3~ 5alk-2-en-l-yl, such as especially allyl, methallyl or dimethylallyl.
Lower alk-2-yn-1-yl is, for example, C3-Csalk-2-yn-l-yl, such as especially prop-2-yn-l-yl or but-2-yn-1-yl.
Lower aLkyl is, for example, Cl-C4alkyl, such as me~yl, ethyl, propyl or bu~l.
Novel thiosemicarbazonic acid esters The invention relates to novel thiosemicarbazonic acid esters of formula I
1~ R4 ~ N S
R I ~C = N ` N ~ C ` N ` R (I) wherein Rl and Rs are lower alkyl, lower aLk-2-en-1-yl or lower alk-2-yn-1-yl, R2 and R3 independently of one another are hydrogen or lower alkyl or together are lower aLIcylidene and R4 is lower alkyl, lower aLkoxy, lower aLk-2-en-1-yl, lower alk-2-yn-1-yl, aryl-lower alkyl, aryl-lower aLkenyl or lower aLI~oxycarbonyl-lower aLIcyl, and to the salts and tautomeric compounds and double-bond isomers thereof, to processes for the preparation of the said compounds, to pharmaceutical compositions comprising them and to their use as active ingredients in medicaments.
Hereinbefore and hereinafter, "lower" radicals and compounds are to be understood as being, for example, those having up to and including 7, preferably up to and including 4, carbon atoms (C atoms).
Lower aL~-2-en-1-yl is, for exarnple, C3~ 5alk-2-en-l-yl, such as especially allyl, methallyl or dimethylallyl.
Lower alk-2-yn-1-yl is, for example, C3-Csalk-2-yn-l-yl, such as especially prop-2-yn-l-yl or but-2-yn-1-yl.
Lower aLkyl is, for example, Cl-C4alkyl, such as me~yl, ethyl, propyl or bu~l.
2~74~2 Lower aL~ylidene is, for example, Cl-C4aLkylidene, such as especially methylene or ethylidene.
Lower aL~oxy is, for example, n-propoxy, isopropoxy, n-butoxy or tert-butoxy, preferably ethoxy, and especially methoxy.
Aryl - in combined terrns such as aryl-lower aLIcyl or aryl-lower aL~cenyl - is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl, or substituted phenyl or naphthyl, such as phenyl or naphthyl substituted by lower alkyl, halo-lower aLI~yl, hydroxy, lower aL~oxy, lower aLI~anoyloxy, halogen, cyano and/or by nitro. Aryl is preferably unsubstituted or is phenyl substituted as indicated above, and is especially phenyl.
Aryl-lower aL~yl is preferably phenyl-lower aLIcyl and especially benz.yl.
Aryl-lower aL~enyl is preferalby phenyl-lower aL~cenyl, especially phenylallyl or phenyl-vinyl (phenylethylenej.
Lower aL~oxycarbonyl-lower aL~cyl is, for example, propoxycarbonyl- or butoxycarbonyl-lower aL~yl, preferably methoxycarbonyl-lower alkyl, and especially ethoxycarbonyl-lower aL~yl, such as metboxycarbonyl- or ethoxycarbonyl-ethyl or -methyl.
Pharmaceutically acceptable acid addition salts of compounds of formula I are, for example, the pharmaceutically acceptable salts tbereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydro-bromides, sulfates, hydrogen sulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamaltes (cyclamates), or salts with strong organic carboxylic acids, such as lower aLkanecarboxylic acids or saturated or unsaturated or hydroxylated aliphatic dicarboxylic acids, for example acetates, oxalates, malonates, maleinates, fumarates, maleates, tartrates or citrates. Salts of compounds of formula I are, for example, the acid addition salts thereof, for example the pharmaceut-ically acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acids or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, ~or example methanesulfonates, benzenesulfonates, 2~97~82 p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).
The compounds of formula I and the pharmaceutically acceptable salts thereof have valuable pharmacological properties. Those properties can be demonstrated in vivo for example using the model of adjuvant arthritis in the rat in accordance with I. Wiesenberg et al., Clin. Exp. Immunol. 78, 245 (1989) in a dosage range of from about 0.1 to about 10.0 mg/kg p.o. or i.p., especially from about 0.1 to about 3.0 mg~g p.o. or i.p..
The compounds of formula I and their pharmaceutically acceptable salts can therefore be used for the treatment of diseases of the rheumatoid type. Those include especially rheumatoid a~thritis, ankylosing spondylitis and other seronegative spondylarthritises, for example spondylarthritis in ulcerative colitis and Crohn's disease, and also reactive ar~sitises, collagen diseases, such as lupus erythematosus, degenerative rheumatic diseases, extra-articular rheumatic and pararheumatic diseases, for example gout and osteoporosis.
The invention relates especially to compounds of formula I wherein Rl and Rs are Cl-C4aLkyl, C3-C5aLk-2-en- l-yl or C3-C5alk-2-yn- l-yl, R2 and R3 independently of one another are hydrogen or Cl-C4alkyl or together are Cl-C4alkylidene and R4 is Cl-C4alkyl, C~-C2aLkoxy, C3-Csalk-2-en-l-yl, C3-Csalk-2-yn-l-yl or phenyl-Cl-C2alkyl, and to the salts and tautomeric compounds and double-bond isomers thereof.
The invention relates more especially to compounds of formula I whereinthe radical Rl is C3-Csalk-2-en-l-yl, such as allyl or methallyl, or C3-Csalk-2-yn-l-yl, such as prop-2-yn-1-yl, R2 and R3 are both hydrogen or identical C~-C4alkyl groups, such as methyl groups, or R2 and R3 together are C l-C4alkylidene, such as methylene, R4 is C~-C4alkyl, such as methyl or ethyl, Cl-C2alkoxy, such as methoxy or ethoxy, C3-C5alk-2-en-l-yl9 such as allyl, methallyl or dimethylallyl, C3-Csalk-2-yn-l-yl, such as prop-2-yn-1-yl, or phenyl-Cl-C2alkyl, such as benzyl, and Rs is C3-Csalk-2-en-l-yl, such as allyl or methallyl, or Cl-C4alkyl, such as methyl or ethyl, and to the salts, especially the pharmaceutically acceptable salts, and tautomeric compounds and double-bond isomers thereof.
2~97~
The invention relates most especially to compounds of formula I, wherein Rl is allyl, methallyl or prop-2-yn-1-yl, R2 and R3 are both hydrogen or methyl, and R4 is allyl, dimethylallyl, prop-2-yn- l-yl or benzyl, and R5 is allyl or methyl, and to the salts, especially the pha~naceutically acceptable salts, and tautomeAc compounds and double-bond isomers thereof.
The invention relates specifically to the compounds of formula I mentioned in the Examples, and to the salts, especially the pharmaceutically acceptable salts, thereof.
The novel compounds of formula I can be prepared in a manner known per se, by reacting a compound of formula II
Rl1 S
O / ~ C N -HN--C~ N--Rs (II) R~f H
with a compound of formula III
R4-X (III) wherein X is a nucleofugal ieaving group and Rl, R2, R3, R4 and Rs are as defined above.
The radical X in a compound of formula III is preferably halogen, for example chlorine, bromine or iodine, but may also be, for example, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy (mesylate) or 4-methylphenylsulfonyloxy (tosylate). As a further leaving group X it is also possible to use, for example, the tri-fluoroacetate group in a compound of formula lII, R4-X.
The condensation of a compound of formula II with a compound of formula III is effected 2~97~
in the presence of a basic condensation agent, such as a tertiary organic base, such as a tri-lower aL~ylamine, for example triethylamine, a Hiinig base or an organic nitrogen base, such as pyridine or quinoline in a temperature range of from 25 to 120~, advantageously at the boiling temperature of the solvent.
There may be used as solvents protic and aprotic solvents, such as aliphatic halogenated hydrocarbons, for example dichloromethane, especially methylene chloride or aliphadc or cycloaliphatic ethers, such as tetrahydrofuran or dioxane. Toluene or ethanol may also be used as solvents.
Where appropriate, salts such as, for example, sodium or potassium iodide and/or catalytic arnounts of dimethylaminopyridine may also be added as reaction accelerators.
The compounds of formula II and processes for the preparation thereof that are based on methods knownper se are known and are described, for example, in GB-l 325 061, US-4 697 020, DE-2 405 395 and DE-2 632 745 and as intermediates in the preparation of turnour-inhibiting medicinal active ingredients.
Compounds obtainable in accordance with the process can be converted in customary manner into other compounds of formula I.
Resulting salts can be converted into the free compounds in a manner known ~ se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or a metal hydrogen carbonate, or with ammonia, or another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another salt-forming acid mentioned at the beginning.
Resulting salts can be converted into different salts in a manner known per se, acid addition salts for example by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and is therefore eliminated from the reaction equilibrium, and base salts by freeing the free acid and converting it into a salt again.
The compounds of formula I7 including their salts, may also be obtained in the forrn of hydrates or may include the solvent used ~or crystallisation.
~7~
In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including the corresponding salts or free compounds, respectively, as appropriate and expedient.
Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-organisms or by reaction of the resulting diastereoisomedc mixture or racemate with an optically active auxiliary compound, for example according to the acidic, basic present in compounds of formula I or an optically active alcohol, to form mixtures of diastereo-isomeric salts or functional derivatives, such as esters, separation of the same into the dia-stereoisomers from which the desired enantiomer can be freed in customary manner.
Bases, acids and alcohols suitable for the purpose are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetarnine and similar bases that can be obtained by synthesis, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D-or L-di-o-toluoyltartaric acid, or optically acdve alcohols, such as borneol or D- or L-(l-phenyl)ethanol.
The invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are ca~ied out, or a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
The invention relates also to the novel starting materials which have been developed specifically for the preparation of the compounds according to ~he invention, especially the group of starting materials that lead to the compounds of formula I mentioned at the beginning as being preferred, to the processes for their preparation and to their use as intermediates.
The pharmaceutical compositions according to the invention, which comprise the compound according to the invention or pharmaceutically acceptable salts thereof, are for enteral, such as oral, also rectal and parenteral, administration to (a) warm-blooded animal(s), and comprise the pharmacological active ingredient on its own or together with a pharmaceutically acceptable carrier. The daily dose of active ingredient is dependent on the age and individual condition as well as on the mode of administration.
~0~74~
The novel pharmaceutical compositions comprise, for example, from about 10 % to about 80 %, preferably from about 20 % to about 60 %, active ingredient. Pharmaceutical compositions according to the invention for enteral and/or parenteral administration are, for example, those in unit dose form, such as dragées, tablets, capsules or suppositories, as well as ampoules. They can be prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting rnixture, and, if desired, processing the mixture or granules, if necessary with the addition of suitable excipients, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for exarnple lactose, saccharose, mannitol or sorbitol, cellulose preparations andlor calcium phosphates, for exarnple tri-calcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrators, such as the above-rnentioned starches, also carboxymethyl st~rch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow agents, flow conditioners and lubricants~ for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose prepara-tions, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.
Other orally administrable pharmaceutical compositions are dry-filled capsules comprising gelatin, and also soft sealed capsules comprising gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycol, to which stabili~sers may also 2~7~ ~
have been added.
Suitable rectally administrable pharmaceutical compositions are, for example, supposit-ories that consist of a combination of the active ingredient with a suppository base. Suit-able suppository bases are, for example, natural or synthetic triglycerides, paraffin hydro-carbons, polyethylene glycol or higher aLkanols. There may also be used gelatin rectal capsules, which comprise a combinadon of the active ingredient with a base material.
Sui~ble base materials are, for example, liquid triglycerides, polyethylene glycol or paraffin hydrocarbons.
Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soloble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.
The invention relates a1so to the use of the compound of formula I, preferably in the form of pharmaceutical compositions. The dose of active ingredient is dependent on the species of warm-blooded animal, the age and the individual condition, as well as on the mode of administration. In normal cases, the approximate daily dose in ~e case of oral adminis-tration to a patient weighing about 75 kg is estimated to be from about 5 mg to about 1000 mg, especially approximately from 10 mg to 200 mg. The dose can be administered all at once or may be divided into several, for example from 2 to 4, individual doses.
Pharmaceutical compositions in unit dose form thus comprise from about 5 mg to about 250 mg, especially from about 10 mg to 50 mg, of active ingredient.
The Examples that follow serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar.
Example 1: With stirring at room temperature, 1.5 g of allyl bromide are added to 2.5 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of methylene chloride and the resuldng mixture is heated to the boiling point of the solvent and maintained under reflux for 4 hours. After cooling to room temperature, the solvent is removed using a rotary evaporator and the resulting residue is taken up in methylene 2~9~
chloride, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. Crystallisation from ether/petroleum ether and further recrystallisation from ethanol yield pure 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester having a m.p. of 117-118C.
Example 2: With stirring at room temperature, 0.75 g of dimethylallyl bromide is added in the pre~sence of 0.5 g of triethylamine and a spatula tip of dimethylarninopyridine to 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetra-hydrofuran and the resulting mixture is heated to the boiling point of the solvent and maintained under reflux for 2 hours. After cooling to room temperature, the solvent is removed using a rotary evaporator and the resulting residue is taken up in methylene chloride, washed with water, dried over magnesium sulfate and concentrated. After crystallisation from methylene chloride/ether the crystals are dissolved in acetone, and 1 ml of 6N HCl in ethanol is added thereto. Filtration and drying at room temperature under a high vacuum yield 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemi-carbazonic acid dimethylallyl ester hydrochloride having a m.p. of 119-121C.
Example 3: Analogously to Example 1, 1.2 g of allyl bromide are added to 2.5 g of 1-(5,5-dirnethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-allyl-thiosemicarbazone in 20 ml of methylene chloride and the mixture is then heated under reflux for 12 hours.
After working up as described above under Example 1 the colourless oil is dissolved in ethanol, 1.5 ml of 6N HCl are introduced and ether is added. Filtration yields colourless crystals of l-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-allyl-thiosemi-carbazonic acid allyl ester hydrochloride having a m.p. of 127-129C.
Example 4: Analogously to Example 2, 1.6 g of 1-(5,5-dimethyl-3-methallyl-4-oxo-thia-zolidin-2-ylidene)-4-allyl-thiosemicarbazone in 25 ml of methylene chloride and 0.7 g of methyl iodide are stirred at room temperature for 24 hours in the presence of 0.5 g of triethylamine. Then a further 0.5 g of methyl iodide and 0.3 g of triethylamine are added and the reaction mixture is boiled under reflux for S hours. Working up analogously to Example 2 and chromatography on silica gel with methylene chloride and crystallisation from ether/petroleum ether yield l-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-yl-idene)-4-allyl-thiosemicarbazonic acid allyl ester hydrochloride in a diastereoisomeric ratio of 5:1, m.p. 98-104C.
Example 5: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-2 ~
4-methyl-thiosemicarbazone in 15 ml of methylene chloride and 0.8 g of methyl iodide are heated under reflux for 24 hours in the presence of 1.4 m1 of triethylamine. Working up as described above in Example 2 and chromatography on silica gel yield 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid methyl ester in a diastereo-isomeric ratio of 3:1, m.p. 127-128C.
Example 6: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetrahydrofuran and 0.9 g of benzyl bromide are boiled under reflux for 5 hours in the presence of O.S g of triethylamine. After working up and crystallisation from methylene chloride/ether, the crystals are dissolved in acetone;
1 ml of 6N HCl in ethanol is added thereto, and crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)~-methyl-thiosemicarbazonic acid benzyl ester hydrochloride are obtained therefrom by filtration in a diastereoisomeric ratio of 7:1, m.p. 139-141C.
Example 7: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of ethanol and 1.1 g of 2-bromomethyl-phenyl ether are boiled under reflux for ~4 hours in the presence of 0.5 g of triethylamine and 0.3 g of sodium iodide. Working up and chromatography on silica gel with methylene chloAde and crystallisation from ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 2~phenoxyet'nyl ester having a m.p. of 106-107C.
ExamPle 8: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-~hiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetrahydrofuran and 1.0 g of 3-phenyl-allyl l-bromide are heated under reflux for 10 hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. After working up and crystallisation from methylene chloride/ether, the crystals are dissolved in acetone; 1 ml of 6N HCl in ethanol is added thereto, and, after the addition of ether, colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid styrene ester hydrochloride are obtained therefrom, m.p. 107-110C.
Exarnple 9: Analogously to Example 2, 2.4 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidcne)-4-methyl-thiosemicarbazone in 30 ml of ethanol and 3.2 g of 3-(2,4-dihydroxy-3-propyl-acetophenon-4-yl)-propyl bromide are heated under reflux for 5 hours in the presence of 2.8 ml of triethylarnine and 0.2 g of sodium iodide. Working up and recrystallisation once from ethanol yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-rnethyl-thiosemi-carbazonic acid 3-(2,4-dihydroxy-3-propyl-acetophenon-4-yl)-propyl ester, 2~9~@s~
m.p. 108-110C.
Example 10: Analogously to Example 2, 2 g of 1-(3-allyl4-oxo-~iazolidin-2-ylidene~-4-methyl-thiosemicarbazone and 0.7 ml of bromoethar ol in 30 ml of ethanol are boiled under reflux for 15 hours in the presence of 1.4 ml of triethylamine, a catalytic amount of dimethylaminopyridine and 0.3 g of sodium iodide. Working up and chromatography on silica gel with ethyl acetate and crystallisadon from ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)4-methyl-thiosemicarbazonic acid 2-hydroxyethyl ester in a diastereoisomeric ratio of 10:1, m.p. 103-105C.
Example 11: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidine)-4-methyl-thiosemicarbazone and 1.0 g of 4-fluorobenzyl bromide in 20 ml of tetrahydro-furan are boiled under reflux for 4 hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and chromatography on silica gel with methylene chloride and crystallisation from methylene chloride/ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 4-fluorobenzyl ester in a diastereoisomeric ratio of 6: 1, m.p. 105-106C.
Exarnple 12: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone and 1.1 g of 2-bromomethylbenzonitrile in 20 ml of tetra-hydrofuran are boiled under reflux for S hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and crystallisation from methylene chloride/ether yield colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl`-thiosemicarbazonic acid 2-cyanobenzyl ester in a diastereoisomeric ratio of 4:1, m.p. 151-152C.
Example 13: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone and 0.7 g of propargyl bromide in 20 ml of tetrahydrofuran are boiled under reflux for 4 hours in the presence of O.S g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and chromatography on silica gel with methylene chloride and crystallisation from methylene chloride/ether yield colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 1-propargyl ester in a diastereoisomeric ratio of 3:1, m.p. 91-92C.
Example 14: Tablet~s, each comprising 10 mg of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-2~7~2 4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared as follows:
ComPosition (10 000 tablets) active ingredient 100.0 g lactose 450.0 g potato starch 350.0 g gelatin 10.0 g talcum 60.0 g magnesium stearate 10.0 g silicon dioxide (highly dispersed) 20.0 g ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remainder of the potato starch, the magnesium stearate, the talcum and the silicon dioxide are mixed in and the mixture is compressed to form tablets, each weighing 100.0 mg and comprising 10.0 mg of active ingredient; if desired the tablets may be provided with dividing notches for finer adaptation of the dose.
Example 15: Hard gelatin capsules comprising 20 mg of acdve ingredient, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 capsules) active ingredient 20.0 g lactose 240.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve of 0.2 mm mesh size. The two components are intimately mixed. Then first the lactosR is added through a sieve of 0.6 mm mesh Si7R and then the microcrystalline cellulose is ~7~
added through a sieve of 0.9 mm mesh size. The mixture is then intimately mixed again for 10 minutes. Finally the magnesium stearate is added through a sieve of 0.8 mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatin capsules are each fllled with 300 mg of the resulting formulation.
Example 16: Hard gelatin capsules comprising 100 mg of active ingredient, for example 1-(3-allyl-~oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 capsules) active ingredient 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve of 0.2 mm mesh size. The two cornponents are intimately mixed. Then first the lactose is added through a sieve of 0.6 rnm mesh size and then the microcrystalline cellulose is added through a sieve of 0.9 mm mesh size. The mixture is then intima$ely mixed again for 10 minutes. Finally the magnesium stearate is added through a sieve of 0.8 mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatin capsules are each filled with 390 mg of the resulting for~nulation.
.
Example 17: Film-coated tablets each comprising 50 mg of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 film-coated tablets) active ingredient S0.0 g lactose 100.0 g com starch 70.0 g talcum 10.0 g calcium stearate 2.0 g ~97~
hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s.
methylene chloride q.s.
The acdve ingredient, the lac~ose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating) and granulated.
The granules are dried, the remainder of the corn starch, the talcum and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 240 mg) which are then film-coated with a solution of the hydroxypropylmethyl-cellulose and the shellac in methylene chloAde; final weight of the film-coated tablet:
283 mg.
Example 18: A 0.2 % injecdon or infusion solution of 1-(3-allyl-4-oxo-thiazolidin-2-yl-idene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 ampoules) active ingredient 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g demineralised waterad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added and the solution is made up to 2500 ml with water. For the preparation of unit dose forms, 1.0 ml or 2.5 ml portions are introduced into glass ampoules, which then each comprise 2.0 or 5.0 mg of activeingredient, respectively.
Example 19: A 1 % ointment (o/w emulsion), comprising as active ingredient, for example, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, having the following composition:
active ingredient 1.0 g cetyl alcohol 3.0 g 2~97~ )~
glycerol ~- g methylparaben 0.18g propylparaben 0.05 g Arlacel 60 0.6 g I`ween 60 4.4 g stearic acid 9.0 g isopropyl palmitate 2.0 g paraffin oil, viscous10.0 g demin. water, q.s. ad100.0 g Example 20: A 1 % gel, comprising as active ingredient, for example, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene~-~methyl-thiosemicarbazonic acid allyl ester or a salt thereof, having the following composition:
active ingredient 1.0 g Carbopol 934 P 1.0 g glycerol 3.0 g isopropanol 25.0 g Softigen(~ 767 0.2 g demin. water, q.s. ad100.0 g Example 21: In a manner analogous to that described in the above E~xamples 14 to 20, it is also possible to prepare pharmaceutical compositions comprising a different compound of formula I or a pharmaceutically acceptable salt thereof.
Lower aL~oxy is, for example, n-propoxy, isopropoxy, n-butoxy or tert-butoxy, preferably ethoxy, and especially methoxy.
Aryl - in combined terrns such as aryl-lower aLIcyl or aryl-lower aL~cenyl - is, for example, phenyl or naphthyl, such as 1- or 2-naphthyl, or substituted phenyl or naphthyl, such as phenyl or naphthyl substituted by lower alkyl, halo-lower aLI~yl, hydroxy, lower aL~oxy, lower aLI~anoyloxy, halogen, cyano and/or by nitro. Aryl is preferably unsubstituted or is phenyl substituted as indicated above, and is especially phenyl.
Aryl-lower aL~yl is preferably phenyl-lower aLIcyl and especially benz.yl.
Aryl-lower aL~enyl is preferalby phenyl-lower aL~cenyl, especially phenylallyl or phenyl-vinyl (phenylethylenej.
Lower aL~oxycarbonyl-lower aL~cyl is, for example, propoxycarbonyl- or butoxycarbonyl-lower aL~yl, preferably methoxycarbonyl-lower alkyl, and especially ethoxycarbonyl-lower aL~yl, such as metboxycarbonyl- or ethoxycarbonyl-ethyl or -methyl.
Pharmaceutically acceptable acid addition salts of compounds of formula I are, for example, the pharmaceutically acceptable salts tbereof with suitable mineral acids, such as hydrohalic acids, sulfuric acid or phosphoric acid, for example hydrochlorides, hydro-bromides, sulfates, hydrogen sulfates or phosphates, salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, for example methanesulfonates, benzenesulfonates, p-toluenesulfonates or N-cyclohexylsulfamaltes (cyclamates), or salts with strong organic carboxylic acids, such as lower aLkanecarboxylic acids or saturated or unsaturated or hydroxylated aliphatic dicarboxylic acids, for example acetates, oxalates, malonates, maleinates, fumarates, maleates, tartrates or citrates. Salts of compounds of formula I are, for example, the acid addition salts thereof, for example the pharmaceut-ically acceptable salts thereof with suitable mineral acids, such as hydrohalic acids, sulfuric acids or phosphoric acid, for example hydrochlorides, hydrobromides, sulfates, hydrogen sulfates or phosphates, or salts with suitable aliphatic or aromatic sulfonic acids or N-substituted sulfamic acids, ~or example methanesulfonates, benzenesulfonates, 2~97~82 p-toluenesulfonates or N-cyclohexylsulfamates (cyclamates).
The compounds of formula I and the pharmaceutically acceptable salts thereof have valuable pharmacological properties. Those properties can be demonstrated in vivo for example using the model of adjuvant arthritis in the rat in accordance with I. Wiesenberg et al., Clin. Exp. Immunol. 78, 245 (1989) in a dosage range of from about 0.1 to about 10.0 mg/kg p.o. or i.p., especially from about 0.1 to about 3.0 mg~g p.o. or i.p..
The compounds of formula I and their pharmaceutically acceptable salts can therefore be used for the treatment of diseases of the rheumatoid type. Those include especially rheumatoid a~thritis, ankylosing spondylitis and other seronegative spondylarthritises, for example spondylarthritis in ulcerative colitis and Crohn's disease, and also reactive ar~sitises, collagen diseases, such as lupus erythematosus, degenerative rheumatic diseases, extra-articular rheumatic and pararheumatic diseases, for example gout and osteoporosis.
The invention relates especially to compounds of formula I wherein Rl and Rs are Cl-C4aLkyl, C3-C5aLk-2-en- l-yl or C3-C5alk-2-yn- l-yl, R2 and R3 independently of one another are hydrogen or Cl-C4alkyl or together are Cl-C4alkylidene and R4 is Cl-C4alkyl, C~-C2aLkoxy, C3-Csalk-2-en-l-yl, C3-Csalk-2-yn-l-yl or phenyl-Cl-C2alkyl, and to the salts and tautomeric compounds and double-bond isomers thereof.
The invention relates more especially to compounds of formula I whereinthe radical Rl is C3-Csalk-2-en-l-yl, such as allyl or methallyl, or C3-Csalk-2-yn-l-yl, such as prop-2-yn-1-yl, R2 and R3 are both hydrogen or identical C~-C4alkyl groups, such as methyl groups, or R2 and R3 together are C l-C4alkylidene, such as methylene, R4 is C~-C4alkyl, such as methyl or ethyl, Cl-C2alkoxy, such as methoxy or ethoxy, C3-C5alk-2-en-l-yl9 such as allyl, methallyl or dimethylallyl, C3-Csalk-2-yn-l-yl, such as prop-2-yn-1-yl, or phenyl-Cl-C2alkyl, such as benzyl, and Rs is C3-Csalk-2-en-l-yl, such as allyl or methallyl, or Cl-C4alkyl, such as methyl or ethyl, and to the salts, especially the pharmaceutically acceptable salts, and tautomeric compounds and double-bond isomers thereof.
2~97~
The invention relates most especially to compounds of formula I, wherein Rl is allyl, methallyl or prop-2-yn-1-yl, R2 and R3 are both hydrogen or methyl, and R4 is allyl, dimethylallyl, prop-2-yn- l-yl or benzyl, and R5 is allyl or methyl, and to the salts, especially the pha~naceutically acceptable salts, and tautomeAc compounds and double-bond isomers thereof.
The invention relates specifically to the compounds of formula I mentioned in the Examples, and to the salts, especially the pharmaceutically acceptable salts, thereof.
The novel compounds of formula I can be prepared in a manner known per se, by reacting a compound of formula II
Rl1 S
O / ~ C N -HN--C~ N--Rs (II) R~f H
with a compound of formula III
R4-X (III) wherein X is a nucleofugal ieaving group and Rl, R2, R3, R4 and Rs are as defined above.
The radical X in a compound of formula III is preferably halogen, for example chlorine, bromine or iodine, but may also be, for example, aliphatically or aromatically substituted sulfonyloxy, for example methylsulfonyloxy (mesylate) or 4-methylphenylsulfonyloxy (tosylate). As a further leaving group X it is also possible to use, for example, the tri-fluoroacetate group in a compound of formula lII, R4-X.
The condensation of a compound of formula II with a compound of formula III is effected 2~97~
in the presence of a basic condensation agent, such as a tertiary organic base, such as a tri-lower aL~ylamine, for example triethylamine, a Hiinig base or an organic nitrogen base, such as pyridine or quinoline in a temperature range of from 25 to 120~, advantageously at the boiling temperature of the solvent.
There may be used as solvents protic and aprotic solvents, such as aliphatic halogenated hydrocarbons, for example dichloromethane, especially methylene chloride or aliphadc or cycloaliphatic ethers, such as tetrahydrofuran or dioxane. Toluene or ethanol may also be used as solvents.
Where appropriate, salts such as, for example, sodium or potassium iodide and/or catalytic arnounts of dimethylaminopyridine may also be added as reaction accelerators.
The compounds of formula II and processes for the preparation thereof that are based on methods knownper se are known and are described, for example, in GB-l 325 061, US-4 697 020, DE-2 405 395 and DE-2 632 745 and as intermediates in the preparation of turnour-inhibiting medicinal active ingredients.
Compounds obtainable in accordance with the process can be converted in customary manner into other compounds of formula I.
Resulting salts can be converted into the free compounds in a manner known ~ se, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or a metal hydrogen carbonate, or with ammonia, or another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another salt-forming acid mentioned at the beginning.
Resulting salts can be converted into different salts in a manner known per se, acid addition salts for example by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and is therefore eliminated from the reaction equilibrium, and base salts by freeing the free acid and converting it into a salt again.
The compounds of formula I7 including their salts, may also be obtained in the forrn of hydrates or may include the solvent used ~or crystallisation.
~7~
In view of the close relationship between the novel compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as including the corresponding salts or free compounds, respectively, as appropriate and expedient.
Resulting racemates can also be resolved into the optical antipodes by known methods, for example by recrystallisation from an optically active solvent, with the aid of micro-organisms or by reaction of the resulting diastereoisomedc mixture or racemate with an optically active auxiliary compound, for example according to the acidic, basic present in compounds of formula I or an optically active alcohol, to form mixtures of diastereo-isomeric salts or functional derivatives, such as esters, separation of the same into the dia-stereoisomers from which the desired enantiomer can be freed in customary manner.
Bases, acids and alcohols suitable for the purpose are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(l-phenyl)ethylamine, 3-pipecoline, ephedrine, amphetarnine and similar bases that can be obtained by synthesis, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D-or L-di-o-toluoyltartaric acid, or optically acdve alcohols, such as borneol or D- or L-(l-phenyl)ethanol.
The invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are ca~ied out, or a starting material is used in the form of a salt or, especially, is formed under the reaction conditions.
The invention relates also to the novel starting materials which have been developed specifically for the preparation of the compounds according to ~he invention, especially the group of starting materials that lead to the compounds of formula I mentioned at the beginning as being preferred, to the processes for their preparation and to their use as intermediates.
The pharmaceutical compositions according to the invention, which comprise the compound according to the invention or pharmaceutically acceptable salts thereof, are for enteral, such as oral, also rectal and parenteral, administration to (a) warm-blooded animal(s), and comprise the pharmacological active ingredient on its own or together with a pharmaceutically acceptable carrier. The daily dose of active ingredient is dependent on the age and individual condition as well as on the mode of administration.
~0~74~
The novel pharmaceutical compositions comprise, for example, from about 10 % to about 80 %, preferably from about 20 % to about 60 %, active ingredient. Pharmaceutical compositions according to the invention for enteral and/or parenteral administration are, for example, those in unit dose form, such as dragées, tablets, capsules or suppositories, as well as ampoules. They can be prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
For example, pharmaceutical compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting rnixture, and, if desired, processing the mixture or granules, if necessary with the addition of suitable excipients, to form tablets or dragée cores.
Suitable carriers are especially fillers, such as sugars, for exarnple lactose, saccharose, mannitol or sorbitol, cellulose preparations andlor calcium phosphates, for exarnple tri-calcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrators, such as the above-rnentioned starches, also carboxymethyl st~rch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow agents, flow conditioners and lubricants~ for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragée cores are provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose prepara-tions, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.
Other orally administrable pharmaceutical compositions are dry-filled capsules comprising gelatin, and also soft sealed capsules comprising gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, if desired, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycol, to which stabili~sers may also 2~7~ ~
have been added.
Suitable rectally administrable pharmaceutical compositions are, for example, supposit-ories that consist of a combination of the active ingredient with a suppository base. Suit-able suppository bases are, for example, natural or synthetic triglycerides, paraffin hydro-carbons, polyethylene glycol or higher aLkanols. There may also be used gelatin rectal capsules, which comprise a combinadon of the active ingredient with a base material.
Sui~ble base materials are, for example, liquid triglycerides, polyethylene glycol or paraffin hydrocarbons.
Suitable for parenteral administration are especially aqueous solutions of an active ingredient in water-soloble form, for example in the form of a water-soluble salt, and also suspensions of the active ingredient, such as corresponding oily injection suspensions, there being used suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions that comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, optionally, stabilisers.
The invention relates a1so to the use of the compound of formula I, preferably in the form of pharmaceutical compositions. The dose of active ingredient is dependent on the species of warm-blooded animal, the age and the individual condition, as well as on the mode of administration. In normal cases, the approximate daily dose in ~e case of oral adminis-tration to a patient weighing about 75 kg is estimated to be from about 5 mg to about 1000 mg, especially approximately from 10 mg to 200 mg. The dose can be administered all at once or may be divided into several, for example from 2 to 4, individual doses.
Pharmaceutical compositions in unit dose form thus comprise from about 5 mg to about 250 mg, especially from about 10 mg to 50 mg, of active ingredient.
The Examples that follow serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar.
Example 1: With stirring at room temperature, 1.5 g of allyl bromide are added to 2.5 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of methylene chloride and the resuldng mixture is heated to the boiling point of the solvent and maintained under reflux for 4 hours. After cooling to room temperature, the solvent is removed using a rotary evaporator and the resulting residue is taken up in methylene 2~9~
chloride, washed with saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and concentrated. Crystallisation from ether/petroleum ether and further recrystallisation from ethanol yield pure 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester having a m.p. of 117-118C.
Example 2: With stirring at room temperature, 0.75 g of dimethylallyl bromide is added in the pre~sence of 0.5 g of triethylamine and a spatula tip of dimethylarninopyridine to 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetra-hydrofuran and the resulting mixture is heated to the boiling point of the solvent and maintained under reflux for 2 hours. After cooling to room temperature, the solvent is removed using a rotary evaporator and the resulting residue is taken up in methylene chloride, washed with water, dried over magnesium sulfate and concentrated. After crystallisation from methylene chloride/ether the crystals are dissolved in acetone, and 1 ml of 6N HCl in ethanol is added thereto. Filtration and drying at room temperature under a high vacuum yield 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemi-carbazonic acid dimethylallyl ester hydrochloride having a m.p. of 119-121C.
Example 3: Analogously to Example 1, 1.2 g of allyl bromide are added to 2.5 g of 1-(5,5-dirnethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-allyl-thiosemicarbazone in 20 ml of methylene chloride and the mixture is then heated under reflux for 12 hours.
After working up as described above under Example 1 the colourless oil is dissolved in ethanol, 1.5 ml of 6N HCl are introduced and ether is added. Filtration yields colourless crystals of l-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-allyl-thiosemi-carbazonic acid allyl ester hydrochloride having a m.p. of 127-129C.
Example 4: Analogously to Example 2, 1.6 g of 1-(5,5-dimethyl-3-methallyl-4-oxo-thia-zolidin-2-ylidene)-4-allyl-thiosemicarbazone in 25 ml of methylene chloride and 0.7 g of methyl iodide are stirred at room temperature for 24 hours in the presence of 0.5 g of triethylamine. Then a further 0.5 g of methyl iodide and 0.3 g of triethylamine are added and the reaction mixture is boiled under reflux for S hours. Working up analogously to Example 2 and chromatography on silica gel with methylene chloride and crystallisation from ether/petroleum ether yield l-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-yl-idene)-4-allyl-thiosemicarbazonic acid allyl ester hydrochloride in a diastereoisomeric ratio of 5:1, m.p. 98-104C.
Example 5: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-2 ~
4-methyl-thiosemicarbazone in 15 ml of methylene chloride and 0.8 g of methyl iodide are heated under reflux for 24 hours in the presence of 1.4 m1 of triethylamine. Working up as described above in Example 2 and chromatography on silica gel yield 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid methyl ester in a diastereo-isomeric ratio of 3:1, m.p. 127-128C.
Example 6: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetrahydrofuran and 0.9 g of benzyl bromide are boiled under reflux for 5 hours in the presence of O.S g of triethylamine. After working up and crystallisation from methylene chloride/ether, the crystals are dissolved in acetone;
1 ml of 6N HCl in ethanol is added thereto, and crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)~-methyl-thiosemicarbazonic acid benzyl ester hydrochloride are obtained therefrom by filtration in a diastereoisomeric ratio of 7:1, m.p. 139-141C.
Example 7: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of ethanol and 1.1 g of 2-bromomethyl-phenyl ether are boiled under reflux for ~4 hours in the presence of 0.5 g of triethylamine and 0.3 g of sodium iodide. Working up and chromatography on silica gel with methylene chloAde and crystallisation from ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 2~phenoxyet'nyl ester having a m.p. of 106-107C.
ExamPle 8: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-~hiazolidin-2-ylidene)-4-methyl-thiosemicarbazone in 30 ml of tetrahydrofuran and 1.0 g of 3-phenyl-allyl l-bromide are heated under reflux for 10 hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. After working up and crystallisation from methylene chloride/ether, the crystals are dissolved in acetone; 1 ml of 6N HCl in ethanol is added thereto, and, after the addition of ether, colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid styrene ester hydrochloride are obtained therefrom, m.p. 107-110C.
Exarnple 9: Analogously to Example 2, 2.4 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidcne)-4-methyl-thiosemicarbazone in 30 ml of ethanol and 3.2 g of 3-(2,4-dihydroxy-3-propyl-acetophenon-4-yl)-propyl bromide are heated under reflux for 5 hours in the presence of 2.8 ml of triethylarnine and 0.2 g of sodium iodide. Working up and recrystallisation once from ethanol yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-rnethyl-thiosemi-carbazonic acid 3-(2,4-dihydroxy-3-propyl-acetophenon-4-yl)-propyl ester, 2~9~@s~
m.p. 108-110C.
Example 10: Analogously to Example 2, 2 g of 1-(3-allyl4-oxo-~iazolidin-2-ylidene~-4-methyl-thiosemicarbazone and 0.7 ml of bromoethar ol in 30 ml of ethanol are boiled under reflux for 15 hours in the presence of 1.4 ml of triethylamine, a catalytic amount of dimethylaminopyridine and 0.3 g of sodium iodide. Working up and chromatography on silica gel with ethyl acetate and crystallisadon from ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)4-methyl-thiosemicarbazonic acid 2-hydroxyethyl ester in a diastereoisomeric ratio of 10:1, m.p. 103-105C.
Example 11: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidine)-4-methyl-thiosemicarbazone and 1.0 g of 4-fluorobenzyl bromide in 20 ml of tetrahydro-furan are boiled under reflux for 4 hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and chromatography on silica gel with methylene chloride and crystallisation from methylene chloride/ether yield crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 4-fluorobenzyl ester in a diastereoisomeric ratio of 6: 1, m.p. 105-106C.
Exarnple 12: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone and 1.1 g of 2-bromomethylbenzonitrile in 20 ml of tetra-hydrofuran are boiled under reflux for S hours in the presence of 0.5 g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and crystallisation from methylene chloride/ether yield colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl`-thiosemicarbazonic acid 2-cyanobenzyl ester in a diastereoisomeric ratio of 4:1, m.p. 151-152C.
Example 13: Analogously to Example 2, 1.2 g of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazone and 0.7 g of propargyl bromide in 20 ml of tetrahydrofuran are boiled under reflux for 4 hours in the presence of O.S g of triethylamine and a spatula tip of dimethylaminopyridine. Working up and chromatography on silica gel with methylene chloride and crystallisation from methylene chloride/ether yield colourless crystals of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 1-propargyl ester in a diastereoisomeric ratio of 3:1, m.p. 91-92C.
Example 14: Tablet~s, each comprising 10 mg of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-2~7~2 4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared as follows:
ComPosition (10 000 tablets) active ingredient 100.0 g lactose 450.0 g potato starch 350.0 g gelatin 10.0 g talcum 60.0 g magnesium stearate 10.0 g silicon dioxide (highly dispersed) 20.0 g ethanol q.s.
The active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve.
After drying, the remainder of the potato starch, the magnesium stearate, the talcum and the silicon dioxide are mixed in and the mixture is compressed to form tablets, each weighing 100.0 mg and comprising 10.0 mg of active ingredient; if desired the tablets may be provided with dividing notches for finer adaptation of the dose.
Example 15: Hard gelatin capsules comprising 20 mg of acdve ingredient, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 capsules) active ingredient 20.0 g lactose 240.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve of 0.2 mm mesh size. The two components are intimately mixed. Then first the lactosR is added through a sieve of 0.6 mm mesh Si7R and then the microcrystalline cellulose is ~7~
added through a sieve of 0.9 mm mesh size. The mixture is then intimately mixed again for 10 minutes. Finally the magnesium stearate is added through a sieve of 0.8 mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatin capsules are each fllled with 300 mg of the resulting formulation.
Example 16: Hard gelatin capsules comprising 100 mg of active ingredient, for example 1-(3-allyl-~oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 capsules) active ingredient 100.0 g lactose 250.0 g microcrystalline cellulose 30.0 g sodium lauryl sulfate2.0 g magnesium stearate 8.0 g The sodium lauryl sulfate is added to the lyophilised active ingredient through a sieve of 0.2 mm mesh size. The two cornponents are intimately mixed. Then first the lactose is added through a sieve of 0.6 rnm mesh size and then the microcrystalline cellulose is added through a sieve of 0.9 mm mesh size. The mixture is then intima$ely mixed again for 10 minutes. Finally the magnesium stearate is added through a sieve of 0.8 mm mesh size. After mixing for a further 3 minutes, size 0 hard gelatin capsules are each filled with 390 mg of the resulting for~nulation.
.
Example 17: Film-coated tablets each comprising 50 mg of 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 film-coated tablets) active ingredient S0.0 g lactose 100.0 g com starch 70.0 g talcum 10.0 g calcium stearate 2.0 g ~97~
hydroxypropylmethylcellulose 2.36 g shellac 0.64 g water q.s.
methylene chloride q.s.
The acdve ingredient, the lac~ose and 40 g of the corn starch are mixed and moistened with a paste prepared from 15 g of corn starch and water (with heating) and granulated.
The granules are dried, the remainder of the corn starch, the talcum and the calcium stearate are added and mixed with the granules. The mixture is compressed to form tablets (weight: 240 mg) which are then film-coated with a solution of the hydroxypropylmethyl-cellulose and the shellac in methylene chloAde; final weight of the film-coated tablet:
283 mg.
Example 18: A 0.2 % injecdon or infusion solution of 1-(3-allyl-4-oxo-thiazolidin-2-yl-idene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, can be prepared, for example, as follows:
Composition (for 1000 ampoules) active ingredient 5.0 g sodium chloride 22.5 g phosphate buffer pH = 7.4 300.0 g demineralised waterad 2500.0 ml The active ingredient and the sodium chloride are dissolved in 1000 ml of water and filtered through a microfilter. The buffer solution is added and the solution is made up to 2500 ml with water. For the preparation of unit dose forms, 1.0 ml or 2.5 ml portions are introduced into glass ampoules, which then each comprise 2.0 or 5.0 mg of activeingredient, respectively.
Example 19: A 1 % ointment (o/w emulsion), comprising as active ingredient, for example, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid allyl ester or a salt thereof, having the following composition:
active ingredient 1.0 g cetyl alcohol 3.0 g 2~97~ )~
glycerol ~- g methylparaben 0.18g propylparaben 0.05 g Arlacel 60 0.6 g I`ween 60 4.4 g stearic acid 9.0 g isopropyl palmitate 2.0 g paraffin oil, viscous10.0 g demin. water, q.s. ad100.0 g Example 20: A 1 % gel, comprising as active ingredient, for example, 1-(3-allyl-4-oxo-thiazolidin-2-ylidene~-~methyl-thiosemicarbazonic acid allyl ester or a salt thereof, having the following composition:
active ingredient 1.0 g Carbopol 934 P 1.0 g glycerol 3.0 g isopropanol 25.0 g Softigen(~ 767 0.2 g demin. water, q.s. ad100.0 g Example 21: In a manner analogous to that described in the above E~xamples 14 to 20, it is also possible to prepare pharmaceutical compositions comprising a different compound of formula I or a pharmaceutically acceptable salt thereof.
Claims (20)
1. A compound of formula I
(I) wherein R1 and R5 are lower alkyl, lower alk-2-en-1-yl or lower alk-2-yn-1-yl, R2 and R3 independently of one another are hydrogen or lower alkyl or together are lower alkylidene and R4 is lower alkyl, lower alkoxy, lower alk-2-en-1-yl, lower alk-2-yn-1-yl, aryl-lower alkyl, aryl-lower alkenyl or lower alkoxycarbonyl-lower alkyl, or a salt or tautomeric compound or double-bond isomer thereof.
(I) wherein R1 and R5 are lower alkyl, lower alk-2-en-1-yl or lower alk-2-yn-1-yl, R2 and R3 independently of one another are hydrogen or lower alkyl or together are lower alkylidene and R4 is lower alkyl, lower alkoxy, lower alk-2-en-1-yl, lower alk-2-yn-1-yl, aryl-lower alkyl, aryl-lower alkenyl or lower alkoxycarbonyl-lower alkyl, or a salt or tautomeric compound or double-bond isomer thereof.
2. A compound according to claim 1 of formula I wherein R1 and R5 are C1-C4alkyl, C3-C5alk-2-en-1-yl or C3-C5alk-2-yn-1-yl, R2 and R3 independently of one another are hydrogen or C1-C4alkyl or together are C1-C4alkylidene and R4 is C1-C4alkyl, C1-C2alkoxy, C3-C5alk-2-en-1-yl, C3-C5alk-2-yn-1-yl or phenyl-C1-C2alkyl, or a salt or tautomeric compound or double-bond isomer thereof.
3. A compound according to claim 1 of formula I wherein the radical R1 is C3-C5alk-2-en-1-yl, such as allyl or methallyl, or C3-C5alk-2-yn-l-yl, such as prop-2-yn-1-yl, R2 and R3 are both hydrogen or identical C1-C4alkyl groups, such as methyl groups, or R2 and R3 together are C1-C4alkylidene, such as methylene, R4 is C1-C4alkyl, such as methyl or ethyl, C1-C2alkoxy, such as methoxy or ethoxy, C3-C5alk-2-en-1-yl, such as allyl, methallyl or dimethylallyl, C3-C5alk-2-yn-1-yl, such as prop-2-yn-1-yl, or phenyl-C1-C2alkyl, such as benzyl, and R5 is C3-C5alk-2-en-1-yl, such as allyl or methallyl, or C1-C4alkyl, such as methyl or ethyl, or a pharmaceutically acceptable salt or tautomeric compound or double-bond isomer thereof.
4. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methylthiosemicarbazonic acid allyl ester or a pharmaceutically acceptable salt thereof.
5. A 1-(3-allyl-4-oxo-thiazolin-2-ylidene)-4-methyl-thiosemicarbazonic acid dimethylallyl ester or a pharmaceutically acceptable salt thereof.
6. A 1-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-allyl-thiosemicarbazonic acid allyl ester or a pharmaceutically acceptable salt thereof.
7. A 1-(5,5-dimethyl-3-methallyl-4-oxo-thiazolidin-2-ylidene)-4-allyl-thiosemicarbazonic acid alkyl ester or a pharmaceutically acceptable salt thereof.
8. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid benzyl ester or a pharmaceutically acceptable salt thereof.
9. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid methyl ester or a pharmaceutically acceptable salt thereof.
10. A 1-(3-allyl-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 2-phenoxyethyl ester or a pharmaceutically acceptable salt thereof.
11. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid styrene ester or a pharmaceutically acceptable salt thereof.
12. A 1-(3-ally-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 3-(2,4-dihydroxy-3-propyl-acetophenon-4-yl)-propyl ester or a pharmaceutically acceptable salt thereof.
13. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 2-hydroxyethyl ester or a pharmaceutically acceptable salt thereof.
14. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 4-fluoro-benzyl ester or a pharmaceutically acceptable salt thereof.
15. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid 2-cyano-benzyl ester or a pharmaceutically acceptable salt thereof.
16. A 1-(3-allyl-4-oxo-thiazolidin-2-ylidene)-4-methyl-thiosemicarbazonic acid l-propargyl ester or a pharmaceutically acceptable salt thereof.
17. A compound according to any one of claims 1 to 16 for use in a method for the therapeutic treatment of the human or animal body.
18. A pharmaceutical composition comprising as pharmaceutical active ingredient, in addition to customary pharmaceutical excipients, a compound according to any one of claims 1 to 16 in free form or in the form of a pharmaceutically acceptable salt.
19. A process for the preparation of a novel compound of formula I according to claim 1, which comprises reacting a compound of formula II
(II) with a compound of formula III
R4-X (III) wherein X is a nucleofugal leaving group and R1, R2, R3, R4 and R5 are as defined above, and, if desired, separating a mixture of isomers obtainable in accordance with the invention into the individual isomers and isolating the desired isomer and/or converting a free compound obtainable in accordance with the invention into a salt or converting a salt obtainable in accordance with the invention into the free compound or into a different salt.
(II) with a compound of formula III
R4-X (III) wherein X is a nucleofugal leaving group and R1, R2, R3, R4 and R5 are as defined above, and, if desired, separating a mixture of isomers obtainable in accordance with the invention into the individual isomers and isolating the desired isomer and/or converting a free compound obtainable in accordance with the invention into a salt or converting a salt obtainable in accordance with the invention into the free compound or into a different salt.
20. The process of the Examples, novel starting materials used in accordance with the process, novel intermediates formed in accordance with the process and novel endproducts obtainable in accordance with the process.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1777/92-1 | 1992-06-03 | ||
| CH177792 | 1992-06-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2097482A1 true CA2097482A1 (en) | 1993-12-04 |
Family
ID=4218374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002097482A Abandoned CA2097482A1 (en) | 1992-06-03 | 1993-06-01 | Thiosemicarbazonic acid esters |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5338746A (en) |
| EP (1) | EP0573391A1 (en) |
| JP (1) | JPH0641102A (en) |
| KR (1) | KR940005601A (en) |
| AU (1) | AU664084B2 (en) |
| CA (1) | CA2097482A1 (en) |
| FI (1) | FI932510A (en) |
| HU (1) | HUT68502A (en) |
| IL (1) | IL105888A (en) |
| NO (1) | NO932002L (en) |
| NZ (1) | NZ247748A (en) |
| TW (1) | TW244349B (en) |
| ZA (1) | ZA933849B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU665073B2 (en) * | 1992-06-03 | 1995-12-14 | Ciba-Geigy Ag | Novel thiosemicarbazone derivatives |
| CA2153690A1 (en) * | 1993-11-25 | 1995-06-01 | Martin Missbach | Novel substituted thiosemicarbazonic acid esters |
| RU2375822C2 (en) | 2004-07-29 | 2009-12-10 | Квэлкомм Инкорпорейтед | System and method for time separation |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH511877A (en) * | 1969-07-17 | 1971-08-31 | Ciba Geigy Ag | Process for the production of a new thiosemicarbazone |
| GB1325061A (en) * | 1970-07-03 | 1973-08-01 | Ciba Geigy Ag | Process for the production of azines |
| EP0316723B1 (en) * | 1987-11-20 | 1992-09-30 | Hoechst-Roussel Pharmaceuticals Incorporated | 3-[4(1-Substituted-4-piperazinyl)butyl]-4-thiazolidinones a process for their preparation and their use as medicaments |
| AU658175B2 (en) * | 1991-04-12 | 1995-04-06 | Novartis Ag | Use of 2-iminothiazolidin-4-one derivatives as novel pharmaceutical active ingredients |
| EP0548017A1 (en) * | 1991-12-18 | 1993-06-23 | Ciba-Geigy Ag | Thiazoles |
| AU665073B2 (en) * | 1992-06-03 | 1995-12-14 | Ciba-Geigy Ag | Novel thiosemicarbazone derivatives |
-
1993
- 1993-05-13 AU AU38566/93A patent/AU664084B2/en not_active Ceased
- 1993-05-14 TW TW082103774A patent/TW244349B/zh active
- 1993-05-25 EP EP93810381A patent/EP0573391A1/en not_active Withdrawn
- 1993-06-01 NZ NZ247748A patent/NZ247748A/en unknown
- 1993-06-01 CA CA002097482A patent/CA2097482A1/en not_active Abandoned
- 1993-06-02 FI FI932510A patent/FI932510A/en not_active Application Discontinuation
- 1993-06-02 JP JP5131973A patent/JPH0641102A/en active Pending
- 1993-06-02 ZA ZA933849A patent/ZA933849B/en unknown
- 1993-06-02 HU HU9301617A patent/HUT68502A/en unknown
- 1993-06-02 KR KR1019930009847A patent/KR940005601A/en not_active Application Discontinuation
- 1993-06-02 IL IL10588893A patent/IL105888A/en not_active IP Right Cessation
- 1993-06-02 NO NO932002A patent/NO932002L/en unknown
- 1993-09-15 US US08/121,973 patent/US5338746A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NO932002D0 (en) | 1993-06-02 |
| KR940005601A (en) | 1994-03-21 |
| IL105888A (en) | 1996-12-05 |
| US5338746A (en) | 1994-08-16 |
| AU3856693A (en) | 1993-12-09 |
| FI932510A0 (en) | 1993-06-02 |
| HU9301617D0 (en) | 1993-09-28 |
| ZA933849B (en) | 1993-12-03 |
| IL105888A0 (en) | 1993-10-20 |
| EP0573391A1 (en) | 1993-12-08 |
| NO932002L (en) | 1993-12-06 |
| HUT68502A (en) | 1995-06-28 |
| FI932510A (en) | 1993-12-04 |
| JPH0641102A (en) | 1994-02-15 |
| TW244349B (en) | 1995-04-01 |
| NZ247748A (en) | 1995-08-28 |
| AU664084B2 (en) | 1995-11-02 |
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